Perfluorinated hydrocarbon compounds such as perfluorooctane sulfonate (PFOS) are emerging contaminants of concern. Concentrations of PFOS have been detected in water, house dust and in human serum. PFOS is persistent, bioaccumulative, and highly toxic. Cause for concern is not only driven by the persistence and the documented toxicity, but by the uncertainty and data gaps including mechanisms of effects, exposure routes, kinetics in the body, under representation of populations in the current human biomonitoring data, and lack of understanding of sublethal exposure effects. Many compounds in this class, like PFOS, are PPAR-alpha agonists. We have shown that PFOS inhibits both T-dependent (TDAR) and T-independent (TI) antibody production but this is not altered in PPAR-alpha -/- mice. We have also shown that alterations in IL-4, IL-5, IL-6 and CD40, CD154 expression and signalling are not related to suppression of IgM production. We speculate that IgM suppression may occur through the known suppression of IL-2 production by PPAR-alpha ligands, since IL-2 production is important to both TDAR and TI antibody responses and suppression of antibody production does not occur in PPAR-alpha deficient mice. However, to better understand the complete effects POFS has on the immune system other critical factors associated with antibody production should be assessed. Hypothesis: PFOS suppresses antibody production via altered T-cell IL-2 production but not macrophage cytokine production or altered CD25, CD27, or CD70 expression.
Aim 1. To determine the role of T-cell IL-2, Macrophage IL-1 and IL-10, and CD25, CD27, and CD70 expression in the suppression of antibody production by PFOS in resting (unchallegened) immune cells.
Aim 2. To determine the role of T-cell IL-2, Macrophage IL-1 and IL-10, and CD25, CD27, and CD70 expression in the suppression of antibody production by PFOS in sheep red blood cell challenged (activated) immune cells The unimmunized and immunized experiments will be conducted to control for possible differences in responses related to lymphocyte activation from the immunization used to determine decreased antibody production. The data from this study will aid in hazard assessment of this compound, increase information on mode of action so that the mechanism of action can be determined, and will lead to new information on the role of PPAR-alpha agonists in antibody production.
Determination of the mode and or mechanism or action of PFOS in relation to antibody production is important to human health because: 1) effects on antibody production occur in rodent models at serum concentrations that have been reported in humans, 2) suppression of IgM production is related to increased disease susceptibility, and 3) basing hazard and risk assessments on current data without mechanism of action information would result in no margin of safety;thereby;most likely, overestimating human health risk from exposure. Moreover, understanding the mode or mechanism of effect may also allow identification of markers that can be assessed in humans to better determine true risk as opposed to relative risk derived from rodent studies.